[M(CO)2(NO)], a new core in bioorganometallic chemistry: model complexes of [Re(CO)2(NO)] and [Tc(CO)2(NO)]

In this study selected bidentate (L²) and tridentate (L³) ligands were coordinated to the Re(I) or Tc(I) core [M(CO)₂(NO)]²⁺ resulting in complexes of the general formula fac-[MX(L²)(CO)₂(NO)] and fac-[M(L³)(CO)₂(NO)] (M = Re or Tc; X = Br or Cl). The complexes were obtained directly from the reaction of [M(CO)₂(NO)]²⁺ with the ligand or indirectly by first reacting the ligand with [M(CO)₃]⁺ and subsequent nitrosylation with [NO][BF₄] or [NO][HSO₄]. Most of the reactions were performed with cold rhenium on a macroscopic level before the conditions were adapted to the n.c.a. level with technetium (^99mTc). Chloride, bromide and nitrate were used as monodentate ligands, picolinic acid (PIC) as a bidentate ligand and histidine (HIS), iminodiacetic acid (IDA) and nitrilotriacetic acid (NTA) as tridentate ligands. We synthesised and describe the dinuclear complex [ReCl(μ-Cl)(CO)₂(NO)]₂ and the mononuclear complexes [NEt₄][ReCl₃(CO)₂(NO)], [NEt₄][ReBr₃(CO)₂(NO)], [ReBr(PIC)(CO)₂(NO)], [NMe₄][Re(NO₃)₃(CO)₂(NO)], [Re(HIS)(CO)₂(NO)][BF₄], [⁹⁹Tc(HIS)(CO)₂(NO)][BF₄], [^99mTc(IDA)(CO)₂ (NO)] and [^99mTc(NTA)(CO)₂(NO)]. The chemical and physical characteristics of the Re and Tc-dicarbonyl-nitrosyl complexes differ significantly from those of the corresponding tricarbonyl compounds.     

Exploring the nitrosyl-approach: “Re(CO)2(NO)”- and “Tc(CO)2(NO)”-complexes provide new pathways for bioorganometallic chemistry

Nitrosylation reactions are rare in the context of low valent Re(I)- and Tc(I)-tricarbonyl complexes so far. We herein describe a method for the conversion of a “M(CO)₃-moiety” (M = Re, Tc) into a dicarbonyl-nitrosyl moiety “M(CO)₂NO”, the synthesis of important precursor complexes and intermediates and possible applications for this new kind of Re- and Tc-chemistry.The behavior of the complex [ReCl₃(CO)₂(NO)]⁻ in water was studied in detail and compared to that of [ReCl₃(CO)₃]²⁻. Contrary to the conversion of [ReCl₃(CO)₃]²⁻ to the mixed aquo-carbonyl complex [Re(OH₂)₃(CO)₃]⁺ in water, one chloride remains initially bound to the metal center in the dicarbonyl-nitrosyl complex, making [ReCl(OH₂)₂(CO)₂(NO)]⁺ the main species for further reactions. In this context, we isolated and characterized the complex [Re(μ₃-O)(CO)₂(NO)]₄. Examples of complexes with different bi- and tridentate ligands based on ReCl₃(CO)₂(NO)]⁻ are discussed.For the development of potential new radiopharmaceuticals we also adapted the nitrosylation technique to the n.c.a. level with ^99mTc. [^99mTc(OH₂)₃(CO)₃]⁺ served as starting material to form a ^99mTc(CO)₂(NO)-core. Labelling reactions with ligands such as iminodiacetic acid (IDA), nitrilotriacetic acid (NTA) and diethylenetriamine pentaacetic acid (DTPA) were performed, resulting in the complexes [^99mTc(IDA)(CO)₂(NO)], [^99mTc(NTA)(CO)₂(NO)] and [^99mTc(DTPA)(CO)₂(NO)]. In this way, the “nitrosyl-approach” adds a new and challenging synthetic tool to the already established organometallic chemistry of Re- and Tc-tricarbonyl complexes.     

Complexes of technetium(I) (Tc, Tc) pentacarbonyl core with π-acceptor ligands (tert-butyl isocyanide and triphenylphosphine): Crystal structures of [Tc(CO)5(PPh3)]OTf and [Tc(CO)5(CNC(CH3)3)]ClO4

A procedure was developed for preparing [^99mTcX(CO)₅] (X = Cl, Br, I) in a reasonable yield by high-pressure carbonylation with CO of ^99mTcO₄⁻ in aqueous solutions. In the synthesis, the substantial part of the target product is accumulated in the gas phase and can be transferred from the autoclave into various solvents when relieving the pressure. Compounds [^99mTcX(CO)₅] (X = Cl⁻, Br⁻, I⁻) are stable in solutions for several hours, but in the course of longer storage they gradually decompose to give the tricarbonyl species. Substitution of the halide ligands in [⁹⁹TcX(CO)₅] and [^99mTcX(CO)₅] with tert-butyl isocyanide and triphenylphosphine was studied. The structures of the complexes [Tc(CO)₅(PPh₃)]OTf and [Tc(CO)₅(CNC(CH₃)₃)]ClO₄ are presented.     

Nitridorhenium(V) and nitridotechnetium(V) complexes with 2-(diphenylphoshinomethyl)aniline

Reactions of 2-(diphenylphosphinomethyl)aniline, H₂L¹, with [MNCl₂(PPh₃)₂] complexes (M = Re, Tc) give the bis-chelates [MNCl(H₂L¹)₂]Cl (M = Re, Tc) or the mono-chelate [ReNCl₂(PPh₃)(H₂L¹)] depending on the conditions applied. The aminophosphine reacts as a bidentate, neutral ligand in all three cases. The complexes were studied spectroscopically and by X-ray crystallography.     

Characterization of 99mTc(CO)3-iminodiacetic acid (IDA) and its comparison with 99mTc-(IDA)2 using compounds for hepatobiliary scintigraphy

The organometallic precursor of fac-[^99mTc(CO)₃(H₂O)₃]⁺ has attracted much attention because of the robustness and small size of Tc(I)-tricarbonyl complexes compared to Tc(V) complexes and the good labeling affinity with a variety of donor atoms. Among various ligand systems, an iminodiacetic acid (IDA) was proven as a good chelating group to form a Tc(III)-compelx as well as has been shown its potential as a chelating system for fac-[^99mTc(CO)₃] precursor. In an attempt to confirm the similarity and the difference between ^99mTc(CO)₃-IDA and ^99mTc-(IDA)₂-complex, M(CO)₃-IDA (M = ^99mTc, Re) complexes of disofenin, mebrofenin and N-(3-iodo-2,4,6-trimethyl phenylcarbamoylmethyl) iminodiacetic acid were prepared, and the biological evaluation of ^99mTc(CO)₃-disofenin was performed. The ^99mTc(CO)₃-IDA complexes were prepared with a high radiolabeling yield (>98%) in a quantitative manner and showed a negative charge. The in vivo pharmacokinetic behavior of ^99mTc(CO)₃-disofenin showed a similar biological activity to ^99mTc-(disofenin)₂ in that those complexes were quickly cleared from the blood by the hepatocytes and excreted into the gallbladder and intestine. Accordingly, the ^99mTc(CO)₃-IDA derivatives of disofenin and mebrofenin might be used as hepatobiliary imaging agents. Since an IDA is a promising chelator for ^99mTc-based radiopharmaceutical and the biological properties of ^99mTc(CO)₃-IDA derivative shows similar to that of ^99mTc-complex, a biomolecule containing IDA can be freely radiolabeled with fac-[^99mTc(CO)₃]-precursor or ^99mTc. However, the radiolabeling efficiency and the biological behavior demonstrates the favorable properties of ^99mTc(CO)₃-IDA compound for the development of a new imaging agent.     

Organometallic Tc-technetium(I)- and Re-rhenium(I)-folate derivatives for potential use in nuclear medicine

The folate receptor (FR) is a high affinity membrane protein which is overexpressed on a wide variety of tumor cells, but highly restricted in normal tissues. Therefore folate derivatives labeled with short living isotopes such as ^99mTc (γ, t_1/2 = 6 h) or ¹⁸⁸Re (β⁻, t_1/2 = 17 h) could be used for tumor diagnosis and therapy. In this respect there is a great interest to develop organometallic technetium(I) and rhenium(I) modified folate radiopharmaceuticals. For this purpose folic acid was functionalized with a tridentate picolylamine monoacetic acid chelating system. The chelating system was selectively coupled via an aminohexane spacer to the γ- or α-carboxyl group of the glutamate moiety of folic acid to obtain the corresponding γ- or α-folate derivative or - if directly attached to pteroic acid - the pteroate derivative. The derivatives were reacted with the precursor [M(OH₂)₃(CO)₃]⁺ (M = ^99mTc, Re) to form uniform organometallic folate complexes under mild reaction conditions. All compounds were chemically characterized by means of NMR, MS, IR and HPLC. The determination of the IC₅₀-values for the PAMA-γ-folate derivative (100 nM) and the corresponding organometallic rhenium complex (110 nM) proved retained receptor binding properties. The radiolabeling with [^99mTc(OH₂)₃(CO)₃]⁺ was achieved in excellent yield (>95%) at low ligand concentration (10⁻⁴ M). The cell binding (>45% of total activity) and internalization (>15% of total activity) of all ^99mTc-complexes was very high and specificity for the FR was proved by their complete displacement with excess folic acid. The ^99mTc-complexes were positively tested for their plasma stability and for the absence of binding to plasma proteins.     

Aqueous syntheses of [(Cp-R)M(CO)3] type complexes (Cp = cyclopentadienyl, M = Mn, Tc, Re) with bioactive functionalities

We describe reactions of [^99mTc(H₂O)₃(CO)₃)]⁺ (1) with Diels-Alder products of cyclopentadiene such as “Thiele’s acid” (HCp-COOH)₂ (2) and derivatives thereof in which the corresponding [(Cp-COOH)^99mTc(CO)₃)] (3) complex did form in water. We propose a metal mediated Diels-Alder reaction mechanism. To show that this reaction was not limited to carboxylate groups, we synthesized conjugates of 2 (HCp-CONHR)₂ (4a-c) (4a, R = benzyl amine; 4b, R = N_α-Boc-l-2,3-diaminopropionic acid and 4c, R = glycine). The corresponding ^99mTc complexes [(4a)^99mTc(CO)₃)] 6a, [(4b)^99mTc(CO)₃)] 6b and [(4c)^99mTc(CO)₃)] 6c have been prepared along the same route as for Thiele’s acid in aqueous media demonstrating the general applicability of this synthetic strategy. The authenticity of the ^99mTc complexes on the no carrier added level have been confirmed by chromatographic comparison with the structurally characterized manganese or rhenium complexes.Studies of the reaction of 1 with Thiele’s acid bound to a solid phase resin demonstrated the formation of [(Cp-COOH)^99mTc(CO)₃)] 3 in a heterogeneous reaction. This is the first evidence for the formation of no carrier added ^99mTc radiopharmaceuticals containing cyclopentadienyl ligands via solid phase syntheses. Macroscopically, the manganese analogue 5a and the rhenium complexes 5b-c have been prepared and characterized by IR, NMR, ESI-MS and X-ray crystallography for 5a (monoclinic, P2₁/c, a = 9.8696(2) Å, b = 25.8533(4) Å, c = 11.8414(2) Å, β = 98.7322(17)°) in order to unambiguously assign the authenticity of the corresponding ^99mTc complexes.     

Synthesis and characterization of organometallic rhenium(І) and technetium(І) bile acid complexes

Eight bile acid derivatives have been synthesized with alkyl chains of various length based tridentate ligand chelating system. These derivatives have been reacted with the precursor [Et₄N]₂[Re(CO)₃Br₃] and fac-[M(CO)₃(H₂O)₃]⁺ (M = ^99mTc, Re) in ethanol or ethanol–aqueous media to form water-soluble and stable organometallic complexes in good yields. ¹H NMR, ¹³C NMR, IR and elemental analysis or HRMS spectroscopic analyses confirmed the tridentate complexation of the metal–tricarbonyl fragment exclusively via the tridentate chelates. In addition, the corresponding radioactive technetium-99m complexes were prepared successfully and challenged for stability in physiological phosphate buffer at 37 °C for 24 h. No decomposition of the complexes could be detected under the condition proving the stability of these complexes.     

Synthesis, in vitro and in silico assessment of organometallic Rhenium(I) and Technetium(I) thymidine complexes

Thymidine kinases have been identified as suitable targets for non-invasive imaging of gene therapy and cancer. Thus, there is a high interest in new, reliable and inexpensive radiolabeled thymidine analogues for these applications. In this study we present the synthesis and in vitro evaluation of M(CO)₃-complexes of thymidine (M = ^99mTc, Re) for potential use in SPECT tumor imaging. 5′-amino-5′-deoxythymidine was derivatized at position C5′ with spacers of various lengths (∼0-30 Å) carrying tridentate metal chelating entities such as iminodiacetic acid and picolylamine-N-monoacetic acid. The nucleoside derivatives were reacted with the precursors [ReBr₃(CO)₃]²⁻ and [^99mTc(OH₂)₃(CO)₃]⁺, respectively. The organometallic thymidine complexes have been fully characterized by means of IR, NMR and mass spectrometry. Enzyme kinetic studies revealed mixed inhibition of the human cytosolic thymidine kinase with K_i values ranging from 4.4 to 334 μM for all thymidine complexes. Competitive inhibition of herpes simplex virus type 1 thymidine kinase was only achieved when thymidine and the metal core were separated by a spacer of approximately 30 Å length. These findings were supported by in silico molecular docking and molecular dynamic experiments.     

Synthesis and biological evaluation of a novel 99mTc‐cyclopentadienyltricarbonyl technetium complex as a new potential brain perfusion imaging agent

A new cytectrene prototype of general formula RCpTc(CO)₃ (R = C₆H₅NHCO, Cp = cyclopentadienyl moiety) has been synthesized from N‐phenylferrocenecarboxamide 2 , characterized and evaluated as a potential brain perfusion imaging agent. An improved procedure has been developed to obtain both the ligand 2 , characterized by its solid‐state structure (orthorhombic, Pccn, a = 10.4443(2) Å, b = 26.1467(6) Å, c = 9.9977(3) Å), and the corresponding metallic Tc‐ and Re‐complexes in good yield. These latter complexes possessed similar HPLC retention times, thereby indicating identity of their molecular structures. The Tc‐complex ^99m Tc‐2 is lipophilic enough to cross the blood‐brain barrier. This complex exhibits good brain uptake (1.41% injected dose per gram tissue at 5 min) combined with a fairly good retention of radioactivity in brain (0.48% injected dose per gram tissue after 1 h). Then, the distribution of the activity at 5 min post‐injection in various rat brain regions showed a higher accumulation in the hippocampus area. The new ^99mTc‐cyclopentadienyltricarbonyl technetium complex reported here showed promising biological results, making it an interesting base for the development of a new generation of cytectrene as brain perfusion imaging agent. Copyright © 2011 John Wiley & Sons, Ltd.     

Evaluation and comparison of 99mTc-labeled d-glucosamine derivatives with different 99mTc cores as potential tumor imaging agents

Isocyanide is a strong coordination ligand that can coordinate with [^99mTc(I)(CO)₃]⁺ core and [^99mTc(I)]⁺ core to produce stable ^99mTc complexes, therefore developing a ^99mTc-labeled isocyanide complex for single-photon emission computed tomography (SPECT) imaging is considered to be of great interest. In order to develop potential tumor imaging agents with satisfied tumor uptake and suitable pharmacokinetic properties in vivo, a novel d -glucosamine isocyanide derivative, 4-isocyano-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)butanamide (CN3DG), was synthesized and radiolabeled with [^99mTc(I)]⁺ and [^99mTc(CO)₃]⁺ cores to obtain [^99mTc(CN3DG)₆]⁺ and [^99mTc(CO)₃(CN3DG)₃]⁺ in high radiolabeling yields (>95%). Both of the complexes showed good hydrophilicity and great stability in vitro. Cell uptake studies performed in S180 cells demonstrated they were transported into cells by glucose transporters. Biodistribution studies of the two complexes in mice bearing S180 tumor showed they had high tumor uptakes and rapid clearance from muscle and blood so that the tumor/blood and tumor/muscle ratios were high. By comparison, [^99mTc(CN3DG)₆]⁺ was superior to [^99mTc(CO)₃(CN3DG)₃]⁺ in regard to tumor uptake, tumor/blood and tumor/liver ratios. S180 tumors could be seen clearly from the SPECT/CT images with [^99mTc(CN3DG)₆]⁺. Considering its favorable properties, [^99mTc(CN3DG)₆]⁺ would be a promising tumor imaging agent and needs to be further studied.     

Structure-biodistribution relation of neutral Tc(CO)3-complexes with tridentate N-substituted derivatives of aminoethylglycine and phenylenediamine

Derivatives of ethylenediamine-N-acetic acid (EDAA = N-aminoethylglycine = AEG) and ortho-phenylenediamine-N-acetic acid (PDAA) with uncharged substituents on one or both of the amines form neutral complexes with a [^99mTc(CO)₃]⁺-moiety. We studied the influence of different modifications at the amines (e.g., with methyl, ethyl, butyl or benzyl groups) on the behaviour of the ^99mTc(CO)₃-complexes in vivo in mice, with special focus on blood-brain barrier (BBB) passage. The complexes have been characterised by reversed phase HPLC, log P, electrophoresis and some of them also by LC-MS. Log P values of the ^99mTc-tricarbonyl complexes varied from −0.52 (AEG) to 2.5 (N,N′-dibenzyl-EDAA). With increasing lipophilicity, more of the activity was found in liver and intestines as compared to kidneys and urine for the more polar complexes. Brain uptake was found for the ^99mTc(CO)₃-complexes with N,N′-dibutyl-ethylenediamine-N-acetic acid (0.34% of I.D. after 2 min) and ortho-phenylenediamine-N-acetic acid (0.22% of I.D. after 2 min).     

fac-Acetato-bis(pyrazole) complexes: A systematic study on intra- and intermolecular hydrogen bonds

Acetato-bis(pyrazole) complexes [Mo(η³-methallyl)(O₂CMe)(CO)₂(pz^∗H)₂], (methallyl = CH₂C(CH₃)CH₂) and fac-[M(O₂CMe)(CO)₃(pz^∗H)₂], (pz^∗H = pyrazole or 3,5-dimethylpyrazole, dmpzH; M = Mn, Re) are obtained from [Mo(η³-methallyl)Cl(CO)₂(NCMe)₂] or fac-[MBr(CO)₃(NCMe)₂] [M = Mn (synthesized in situ), Re], 2 equiv. of pyrazole, and 1 equiv. of sodium acetate for Mo complexes, or silver acetate for Mn or Re complexes. The chlorido-complexes [Mo(η³-methallyl)Cl(CO)₂L₂] (L = pzH, dmpzH), obtained from the same starting material by substitution of MeCN by pzH or dmpzH, are also described. The crystal structures of the fac-acetato-bis(dimethylpyrazole) complexes present the same pattern of intramolecular hydrogen bonds between the acetate and the dimetylpyrazole ligands, whereas the crystal structures of the fac-acetato-bis(pyrazole) complexes show different hydrogen bonds patterns, with intermolecular interactions. NMR data indicate that these interactions are not maintained in solution.     

Influence of the ligand donor atoms on the in vitro stability of rhenium(I) and technetium (I)-99m complexes with pyrazole-containing chelators: Experimental and DFT studies

The new pyrazole-containing ligand 3,5-Me₂pz(CH₂)₂S(CH₂)₂COOH (L¹H) was synthesized and used to prepare the complexes fac-[M(κ³-L¹)(CO)₃] (M = Re (1), ^99mTc(1a)), which were obtained in high yield albeit with a low specific activity in the case of ^99mTc. The X-ray diffraction analysis of 1 confirmed that L¹ coordinates to the metal as monoanionic and through a (N,S,O) donor atom set. Challenge experiments of 1a against cysteine and histidine showed that this complex suffers considerable transchelation in vitro. This contrasts with the behavior exhibited by the related complex fac-[^99mTc(κ³-L²)(CO)₃] (2a) (L² = 3,5-Me₂pz-(CH₂)₂NH-CH₂-COO), anchored by a (N₂O)-tridentate ligand. Biodistribution studies of 1a and 2a in mice indicated that both compounds have a relatively similar biological profile. Nevertheless, the fastest blood clearance and minor hepatic retention found for 2a has shown that this complex is more adequate to be further explored in radiopharmaceutical sciences. DFT calculations (ADF program) were performed for these neutral complexes and related cationic M(I) (M = Re, Tc) tricarbonyl complexes anchored by pyrazole-containing ligands, in order to have a better understanding of the influence of the donor atom set (N,N,O vs. N,O,S; N,N,N vs. N,N,S vs. N,S,S) on their in vitro stability. The differences of the calculated binding energies are not significant, suggesting that the in vitro behavior of these Re(I)/Tc(I) tricarbonyl complexes is not determined by thermodynamic factors.     

Chemical and biological evaluation of 99mTc (CO)3 and 99mTc complexes of some IDA derivatives

The confirmation that N-substituted imidodiacetic acids, as small and simple ligand systems containing amines and carboxylic acids, could be coordinated to the tricarbonyl core and form inert complexes with [^99mTc (CO)₃(H₂O)₃]⁺, is demonstrated. The HPLC quality control results of ^99mTc-carbonyl tagged IDA molecules, performed by gradient HPLC, have shown that HIDA, EHIDA and p-butyl-IDA form complexes with [^99mTc(CO)₃(H₂O)₃]⁺, with a labeling yield of ~90% for each of ^99mTc(CO)₃ IDA derivatives. However, the changes in the structure of labeled compounds, e.g., EHIDA, influence the changes in the biological behavior. In comparison with ^99mTc-EHIDA, the biliary excretion of ^99mTc(CO)₃ EHIDA was lower, but the urinary excretion higher. This revised version was published online in July 2006 with corrections to the Cover Date.     

Preparation and biological evaluation of Tc-CO-MIBI as myocardial perfusion imaging agent

^99mTc-Sestamibi has been playing an important role in the cardiac imaging for the last decades. Previously, we reported that [^99mTc(CO)₃(MIBI)₃]⁺ demonstrated a significant location in myocardium with a lower liver uptake as compared with ^99mTc-Sestamibi. In this work, we found that new [^99mTc(CO)₂(MIBI)₄]⁺ could be prepared with high radiochemical purity. The inter-transformations between [^99mTc(CO)₃(H₂O)(MIBI)₂]⁺, [^99mTc(CO)₃(MIBI)₃]⁺, and [^99mTc(CO)₂(MIBI)₄]⁺ were investigated and biodistribution was performed to evaluate the [^99mTc(CO)₂(MIBI)₄]⁺ as a myocardial perfusion imaging agent. The results showed that one more CO was replaced by MIBI slowing down the pharmacokinetics. The structure characterization was performed on their corresponding rhenium complexes, and the results indicated that there were differences between ^99mTc-CO-MIBI and Re-CO-MIBI in preparation and hydrophobic characteristics.     

Radiosynthesis and evaluation of novel [99mTc(I)]+ and [99mTc(I)(CO)3]+ complexes with a 4-nitroimidazole isocyanide for imaging tumor hypoxia

[^99mTc(I)]⁺ and [^99mTc(I)(CO)₃]⁺ complexes with isocyanide exhibit high stability, which makes them suitable platforms to develop novel ^99mTc radiopharmaceuticals. To develop novel ^99mTc radiotracers for imaging hypoxia, in this study, a novel L ligand (4-nitroimidazole isocyanide derivative) was synthesized and labelled using [^99mTc(I)]⁺ core and [^99mTc(I)(CO)₃]⁺ core to produce [^99mTc(L)₆]⁺ and [^99mTc(CO)₃(L)₃]⁺ with high yields. To verify the structure of the ^99mTc complexes, corresponding rhenium analogues were synthesized and characterized. Both of the ^99mTc complexes were stable and hydrophilic. in vitro cellular uptake results showed they could exhibit good hypoxic selectivity. The evaluation of biodistribution in mice bearing S180 tumors indicated both of them could accumulate in tumor. Between them, [^99mTc(L)₆]⁺ exhibited higher tumor uptake and tumor/non-target ratio than [^99mTc(CO)₃(L)₃]⁺. Further, single photon emission computed tomography (SPECT) imaging studies of [^99mTc(L)₆]⁺ indicated an obvious accumulation in tumor and the value of the region-of-interest (ROI) ratio of the uptake for the tumor site to the corresponding non-tumor region was 5.64 ± 0.52. The above results suggested [^99mTc(L)₆]⁺ would be a potential tracer for imaging tumor hypoxia.     

Preparation and protonation reactions of aryl complexes of manganese and rhenium

Aryl M(κ¹-Ar)(CO)_nP_5−n [M = Mn, Re; Ar = C₆H₅, 4-CH₃C₆H₄; n = 2, 3; P = P(OEt)₃, PPh(OEt)₂, PPh₂OEt] and Re(κ¹-C₆H₅)(CO)₃[Ph₂PO(CH₂)₃OPPh₂] complexes were prepared by allowing hydrides MH(CO)_nP_5−n to react first with triflic acid and then with the appropriate aryl lithium (LiAr) compounds. The complexes were characterized spectroscopically (IR and ¹H, ³¹P, ¹³C NMR) and by the X-ray crystal structure determination of Re(κ¹-C₆H₅)(CO)₃[Ph₂PO(CH₂)₃OPPh₂] derivative. Protonation reaction of the aryl complexes with HBF₄ · Et₂O lead to free hydrocarbons Ar-H and the unsaturated [M(CO)_nP_5−n]⁺ cations, separated as solids in the case of [Re(CO)₃P₂]BF₄ derivatives.     

Novel Carbohydrate‐Appended Metal Complexes for Potential Use in Molecular Imaging

Seven discrete sugar‐pendant diamines were complexed to the {M(CO)₃}⁺ (^99mTc/Re) core: 1,3‐diamino‐2‐propyl β‐D ‐glucopyranoside ( L ¹ ), 1,3‐diamino‐2‐propyl β‐D ‐xylopyranoside ( L ² ), 1,3‐diamino‐2‐propyl α‐D ‐mannopyranoside ( L ³ ), 1,3‐diamino‐2‐propyl α‐D ‐galactopyranoside ( L ⁴ ), 1,3‐diamino‐2‐propyl β‐D ‐galactopyranoside ( L ⁵ ), 1,3‐diamino‐2‐propyl β‐(α‐D ‐glucopyranosyl‐(1,4)‐D ‐glucopyranoside) ( L ⁶ ), and bis(aminomethyl)bis[(β‐D ‐glucopyranosyloxy)methyl]methane ( L ⁷ ). The Re complexes [Re( L ¹ – L ⁷ )(Br)(CO)₃] were characterized by ¹H and ¹³C 1D/2D NMR spectroscopy which confirmed the pendant nature of the carbohydrate moieties in solution. Additional characterization was provided by IR spectroscopy, elemental analysis, and mass spectrometry. Two analogues, [Re( L ² )(CO)₃Br] and [Re( L ³ )(CO)₃Br], were characterized in the solid state by X‐ray crystallography and represent the first reported structures of Re organometallic carbohydrate compounds. Conductivity measurements in H₂O established that the complexes exist as [Re( L ¹ – L ⁷ )(H₂O)(CO)₃]Br in aqueous conditions. Radiolabelling of L ¹ – L ⁷ with [^99mTc(H₂O)₃(CO)₃]⁺ afforded in high yield compounds of identical character to the Re analogues. The radiolabelled compounds were determined to exhibit high in vitro stability towards ligand exchange in the presence of an excess of either cysteine or histidine over a 24 h period.     

Rhenium(I) and technetium(I) fac-M(NSO)(CO)3 (M = Re,Tc) tricarbonyl complexes,with a tridentate NSO bifunctional agent: Synthesis,structural characterization,and radiochemistry

The synthesis and structural characterization of the neutral rhenium complex fac-[Re(NSO)(CO)₃], Re-1, where (NSO) is a tridentate bifunctional chelating agent, 3-(carboxymethylthio)-3-(1H-imidazol-4-yl)propanoic acid (1), is presented. The complex crystallized from methanol–water and its structure was assigned by IR and ¹H, ¹³C NMR spectroscopies and X-ray crystallography. Furthermore, the analogous technetium complex fac-[^99mTc(NSO)(CO)₃], ^99mTc-1, was synthesized in high yield by reacting ligand 1 with the fac-[^99mTc(OH₂)₃(CO)₃]⁺ precursor for 30 min at 85 °C. The tracer complex was found to be more than 95% stable in the L-histidine challenge experiment. Our data indicate that the bifunctional NSO chelating agent 1 can be successfully applied for the development of potential ^99mTc-radiopharmaceuticals.